The invention relates to novel oligosaccharides, their preparation by organic synthesis and their biological applications.
This relates to a development of an invention which gives the subject of U.S. patent application Ser. No. 457,931 of Jan. 14, 1983. In this patent application, a process is described for obtaining by organic synthesis oligosaccharides having the structure of fragments of natural acid mucopolysaccharide chains, and derivatives of these oligosaccharides. It is recalled that the expression "acid mucopolysaccharide" denotes derivatives also currently called glycosaminoglycuronoglycans. These derivatives are formed from oligosaccharides and polysacharides constituting more especially chains of biologically active derivatives such as those of the heparin or heparane-sulfate type. These chains are essentially formed from alternate amino-sugar--uronic acid units, or conversely. In these units, the amino-sugar has more especially a D-glucosamine structure (or a) and the uronic acid a D-glucuronic acid structure (or b) or L-iduronic acid structure (or c).
The great flexibility of the process described in the principal patent application enables the preparation of the desired enchainment of the units, in the desired stereochemistry and with predetermined substitutions. It is thus possible to obtain particularly oligosaccharides constituting anologs of the structure of heparin chain fragments.
These fragments can advantageously include the octasaccharide enchainment ABCDEFGH, obtained previously by applicants by enzymatic depolymerization of structure I. ##STR2##
The oligosaccharides obtained synthetically can also include only one portion of this enchainment, or be constituted by this enchainment.
The letters A to H indicated in the formula, denote, as used in the description, one type of structure, substitutions being identical or different from those of the formula.
As described in this principal patent application, the developed oligosaccharides constitute biological reagents and reference substances which are particularly interesting. They are, in addition, endowed with pharmacological properties conferring on them a utility of great importance as an active principle of medicaments.
Certain of these oligosaccharides are revealed more especially to be active in the field of blood clotting.
Thus, if an anti-Xa activity (measured by the Yin-Wessler titer) has been detectable in a trisaccharide of structure DEF, it is with a pentasaccharide of structure DEFGH that it was possible to demonstrate a very high affinity for anti-thrombin III or ATIII and a very high anti-Xa activity (Yin-Wessler) of at least 2000 units Yin-Wessler/mg.
This product corresponds to the following formula: ##STR3##
An anti-Xa activity of at least 2000 Yin-Wessler units/mg could be demonstrated.
In continuing their research, the inventors have now observed surprisingly, a sufficiently high activity to permit the exploitation as active principal of an anti-thrombotic medicament in a group of lower oligosaccharides (this term "lower" being understood with respect to the pentasaccharides).
The extension of this research has led them to develop a specific oligosaccharide group which is shown to be endowed advantageously with a wide therapeutic spectrum.
It is therefore an object of the invention to provide a novel group of oligosaccharides with short chains, whose structure corresponds to that of acid mucopolysacharide chain fragments, or include such fragments.
It is also an object of the invention to provide biological uses of these oligosaccharides as laboratory reagents and as an active principal of medicaments.